Azidothymidine (AZT) as a Potential Modifier of Radiation Response in Vitro

The potential effect of AZT as a thymidine analogue on radiation response in vitro was investigated. Two human cell lines (WiDr and HeLa) were used. The effect of 10 μM AZT on exponentially growing cells was studied after different exposure times (24, 48 and 72 h). The surviving fraction (clonogenic assay) or metabolic activity (MTT assay) after irradiation of AZT-exposed cells, was compared to unexposed irradiated controls. Flow cytometry was used to assess the cell-cycle effect of pre-exposure of exponentially growing cells to AZT. AZT had a radioprotective effect for all experimental time points as far as WiDr was concerned. For HeLa the effect was significant at 24 h. Cell-cycle analysis showed a significant accumulation in S-phase at 72 h for WiDr. For HeLa there was a significant accumulation in S-phase at 48 h. We conclude that under the reported experimental conditions, AZT as a thymidine analogue seems to reduce the cytotoxic effect of irradiation.     

Early benefits of pravastatin to experimentally induced atherosclerosis

There is little information regarding the time of hypolipidemic treatment of changes in atherosclerotic plaque, tissue cholesterol content, and also for the recovery of endothelial function. To assess the early effects of lipid-lowering treatment on these parameters, six groups of New Zealand male rabbits were studied. Animals in groups I and II were fed regular chow; groups III and IV received a 12-week 0.5% cholesterol diet followed by 12 weeks of 0.05% cholesterol diet. Finally, groups V and VI were fed a 12-week 0.5% cholesterol diet and were then shifted to a regular diet for 12 weeks. During the last four weeks, the rabbits in groups I, III, and V received low-dose pravastatin (2 mg/day), added to the diet. Group IV animals had the highest cholesterol plasma levels (vs. groups I, II, III, and V, p < 0.01) and presented atherosclerotic plaques in a more advanced stage. Nonatherogenic diet was insufficient to restore endothelial function in animals previously fed cholesterol-enriched diets (groups IV and VI). Conversely, pravastatin treatment promoted significant improvement in endothelial function and reduced the progression of atherosclerosis. Marked increase in cholesterol content was seen in aorta and liver in response to the atherogenic diet. However, neither treatment with pravastatin nor nonatherogenic diet was capable of modifying the tissue cholesterol content. Our study supports the hypothesis that the early use of statins can attenuate the progression of atherosclerosis and ameliorate endothelial function. In addition, significant changes in the tissue cholesterol pool probably need a longer period of treatment.     

Clinical pharmacokinetics of intranasal sumatriptan

A substantial proportion of migraine patients have gastric stasis and suffer severe nausea and/or vomiting during their migraine attack. This may lead to erratic absorption from the gastrointestinal tract and make oral treatment unsatisfactory. For such patients, an intranasal formulation may be advantageous. Sumatriptan is a potent serotonin 5HT(1B/1D) agonist widely used in the treatment of migraine; the effectiveness of the intranasal formulation (20mg) has been well established in several clinical studies. This article reviews the pharmacokinetics of intranasal sumatriptan and includes comparisons with oral and subcutaneous administration. After intranasal administration, sumatriptan is directly and rapidly absorbed, with 60% of the maximum plasma concentration (C(max)) occurring at 30 minutes after administration of a single 20mg dose. Following intranasal administration, approximately 10% more sumatriptan is absorbed probably via the nasal mucosa when compared with oral administration. Mean C(max) after a 20mg intranasal dose is approximately 13.1 to 14.4 ng/mL, with median time to C(max) approximately 1 to 1.75 hours. When given as a single dose, intranasal sumatriptan displays dose proportionality in its extent of absorption and C(max) over the dose range 5 to 10mg, but not between 5 and 20mg for C(max). The elimination phase half-life is approximately 2 hours, consistent with administration by other routes. Sumatriptan is metabolised by monoamine oxidase (MAO; predominantly the A isozyme, MAO-A) to an inactive metabolite. Coadministration with a MAO-A inhibitor, moclobemide, leads to a significant increase in sumatriptan plasma concentrations and is contraindicated. Single-dose pharmacokinetics in paediatric and adolescent patients following intranasal sumatriptan were studied to determine the effect of changes in nasal morphology during growth, and of body size, on pharmacokinetic parameters. The pharmacokinetic profile observed in adults was maintained in the adolescent population; generally, factors such as age, bodyweight or height did not significantly affect the pharmacokinetics. In children below 12 years, C(max) is comparable to that seen in adolescents and adults, but total exposure (area under the concentration-time curve from zero to infinity) was lower in children compared with older patients, especially in younger children treated with 5mg. Clinical experience suggests that intranasal sumatriptan has some advantages over the tablet (more rapid onset of effect and use in patients with gastrointestinal complaints) or subcutaneous (noninvasive and fewer adverse events) formulations.     

View of the different social agents on the social participation in the health system in northeastern Brazil. A qualitative approximation

BACKGROUND: Social participation in the health system constitutes one of the basic principles of Brazilian health sector reform. This paper analyses the concepts held by different groups of stakeholders with respect to social participation in health and identifies their opinions on hindering and enabling factors for this participation. METHODS: A qualitative study was conducted using individual interviews (II) and focus groups (FG) with different groups of stakeholders: 135 users (II, GF), 14 community leaders (II, GF), 12 Municipal Health Council (MHC) members (II), 8 policymakers and (II) 37 health personnel (II, GF) were interviewed. A narrative content analysis of the results was conducted. Two municipalities in North-eastern Brazil, Cabo de Santo Agostinho and Camaragibe, made up the area of study. RESULTS: In all groups, a distinction between individual and group participation emerged and reached different levels of elaboration. Many informants' ideas described also their own ways of action. Individual participation concepts and the utilization of health services were predominant among users. Population and institutional factors were identified as obstacles to participation: users and community leaders referred both type of factors, while the health personnel and MHC members put more emphasis on the former. Some informants among the health personnel did not identify any barriers. Policymakers emphasised the lack of political will. The enabling factors mentioned reflected the same logic. CONCLUSIONS: Concepts and perceived hindering factors to participation which were described appear to show different ways of interaction among the diverse stakeholders and the health services. The results point towards a limited effect of the health policy on social participation. Elements that could contribute to an improvement are identified.     

Long-term complete haematological and molecular remission after allogeneic bone marrow transplantation in a patient with a stem cell myeloproliferative disorder associated with t(8;13)(p12;q12)

A rare atypical myeloproliferative disorder (aMPD) associated with chromosomal translocations involving the short arm of chromosome 8, region p11-p12 has been described. In most patients, the cytogenetic abnormality is a t(8;13)(p12;q12) that fuses fibroblast growth factor receptor 1, the 8p12 key gene, to FIM/ZNF198 gene. Prognosis is poor with frequent evolution to acute myeloid leukaemia within 1 year of diagnosis. We report a new patient with aMPD with a t(8;13) translocation. Complete haematological, cytogenetic and molecular remission was demonstrated 39 months after allogeneic bone marrow transplantation. This is the first report to demonstrate a molecular remission in this disorder.     

Outcome of surgical treatment in familial mesial temporal lobe epilepsy

PURPOSE: To describe postoperative outcome in patients with familial mesial temporal lobe epilepsy (FMTLE). METHODS: We studied FMTLE patients who underwent surgical treatment for refractory seizures. FMTLE was defined when at least two individuals in a family had a clinical EEG diagnosis of MTLE. Preoperative investigation included magnetic resonance imaging (MRI), interictal/ictal EEGs, and neuropsychological evaluation. We used Engel's classification for postoperative outcome. RESULTS: To date, 20 FMTLE patients have been operated on, with 1.6 to 9.8 years of follow-up (mean, 5.5 years). Hippocampal atrophy (HA) and other signs of mesial temporal sclerosis (MTS) were present in 18 patients (15 unilateral). Seizures were recorded in 19 patients. Seventeen (85%) patients are in class I. Two patients had normal hippocampal volumes (HcV): one (5%) is in class II and the other (5%) in class IV (extratemporal seizures developed after surgery). One (5%) patient had bilateral HA and is in class III. Qualitative histopathology showed MTS with different degrees of severity. CONCLUSIONS: Refractory FMTLE patients have good surgical outcome when unilateral or clearly asymmetric HA is identified. Preoperative investigation should be the same as that in patients with sporadic refractory MTLE.     

Texture analysis of hippocampal sclerosis

Mesial temporal lobe epilepsy (MTLE) is frequently associated with refractory seizures and pathologic features of hippocampal sclerosis (HS). Quantitative magnetic resonance imaging (MRI) techniques can improve the detection and quantification of HS. The objective of this study was to evaluate whether MRI texture analysis can detect hippocampal abnormalities in patients with pathologically proven HS. METHODS: Nineteen consecutive patients who underwent surgery for refractory unilateral MTLE and had HS diagnosed on histopathology (12 right and seven left) had their preoperative MRIs evaluated. We performed texture analysis in 3-mm coronal T1-IR MRIs, focusing on the hippocampal head, by using the software MAZDA. Data were compared with those of a group of 78 normal hippocampi from 39 healthy adult volunteers through multivariate analysis of variance and selection of the most significant texture parameters. RESULTS: Overall, almost all parameters of texture could discriminate the group of hippocampi with HS and the group of contralateral hippocampi from the group of normal hippocampi, but the post hoc comparison showed no differences between HS and contralateral hippocampi. CONCLUSIONS: These results provide evidence of texture alteration in MRIs of hippocampi with HS and corroborate the hypothesis of bilaterality of hippocampal damage in patients with MTLE, but further studies are needed to investigate the lateralization power of texture analysis.     

Marfan's syndrome: early and severe form in siblings

Marfan's syndrome is an inherited disorder of the connective tissue. Cardiologic manifestations, especially aortic dilation, are important causes of morbidity and mortality in the clinical course of the disease in adults and teenagers. In children, the presence of aortic aneurysm and its dissection or rupture is rare, occurring in patients with genetic mutation of the fibrillin gene but not in those who have the familial form of the disease. We describe here 2 patients, from the same family (siblings), diagnosed with gigantic aortic aneurysm early in infancy, one of them successfully undergoing surgery.     

Mitochondrial electron transport chain function is enhanced in inspiratory muscles of patients with chronic obstructive pulmonary disease

In chronic obstructive pulmonary disease, inspiratory muscles face increased resistive and elastic workloads and therefore increased energy requirements. The adaptive response of these muscles to this higher energy demand includes increased oxidative enzymes and changes in contractile protein expression but the consequences on mitochondrial function and energy metabolism have not been assessed so far. We investigated the in situ properties of the mitochondria of costal diaphragm and external intercostal muscles using the skinned fiber technique in 9 emphysematous and 11 age-matched control patients. Biopsies obtained during thoracic surgery were placed in an oxygraphic chamber to measure maximal oxygen uptake. We observed that the maximal oxidative capacity of diaphragm and external intercostal muscles increased significantly in the emphysematous group compared with the control group (+135 and +37%, respectively). Significant correlations were found between the maximal oxidative capacity and patients' pulmonary indexes of obstruction (diaphragm: r = -0.637, intercostal: r = -0.667, p < 0.005) and hyperinflation (diaphragm: r = 0.639, p < 0.003, intercostal: r = 0.634, p < 0.01). Slow myosin heavy chain isoform increased in the diaphragm of the emphysematous group, with significant relationships between indexes of obstruction and hyperinflation and activities of biochemical mitochondrial markers. Thus, severe emphysema was associated with increased mitochondrial capacity and efficiency in the inspiratory muscles, supporting an endurance training-like effect.